Naphthalimido derivatives as antifolate thymidylate synthase inhibitors

A new series of N-(substituted)benzyl-1,8-naphthalimides 4, structurally related to the previously reported thymidylate synthase (TS) inhibitor naphthaleins 3, were synthesized and compounds tested for their inhibition of several species of TS. Moreover, their in vitro cytotoxicity together with antimycotic and antibacterial properties were assayed. While no activity was detected in the antibacterial tests, the m-nitro (4ae) and the p-nitro (4af) derivatives were found able to partially inhibit TS at low micromolar concentrations. Introduction of nitro or (substituted)-amino groups in position 4 of the naphthalic ring always led to less active compounds.     

Blood aggregation in duodenal ulcer

Thirty-six children with duodenal ulcer were examined for the coagulation and thrombocytic components of hemostasis. Use was made of the new coagulologic research methods based on administration of the synthetic tri- and tetrapeptides containing a chromoform group. The high sensitivity of the synthetic peptides enables the use of plasma in high dilutions, owing to which the effect of inhibitors is decreased and a small amount of blood is only required, being of paramount importance in carrying out serial tests. In acute ulcer 1/3 of the children show the signs of the DIC syndrome compensated at the expense of the high content of anticoagulants. At the same time 4 patients were discovered to have coagulologic disorders characteristic of Willebrand's disease (3 cases) and thrombasthenia (1 case). The coagulologic alterations should be taken into consideration in treatment administration, since the compensated DIC syndrome untreated by anticoagulant therapy aggravates the course of the ulcerous process and gives rise to hemorrhagic diathesis. Meanwhile in children with hemorrhagic diathesis, peptic ulcer may cause severe, life-threatening hemorrhages.     

Critical ovarian hyperstimulation syndrome in a coasted in-vitro fertilization patient

We report an instance of critical ovarian hyperstimulation syndrome in a highly responsive in-vitro fertilization patient despite the preventive measure of a 4 day 'coast' interval during which no gonadotrophins were administered while gonadotrophin-releasing hormone agonist therapy continued until serum oestradiol concentrations fell below 3000 pg/ml.      

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Hypertension secondary to progressive vascular neurofibromatosis

A 4 year old girl with neurofibromatosis type 1 (NF1) was referred for hypertension. An aortogram showed narrowing of the left main renal artery. An angiogram three and a half years later showed coarctation of the abdominal aorta. She underwent aortoplasty but the stenosis recurred. Vascular involvement in NF1 may be progressive and requires long term follow up.     

Paradoxical embolization via a patent foramen ovale following acute pulmonary embolism

The foramen ovale is usually obliterated following establishment of the adult circulation but remains patent in 25% of individuals. This potential communication between the venous and arterial circulations can allow thromboembolic material to bypass the lungs and enter the systemic circulation. We report two cases of paradoxical embolization through a patent foramen ovale following acute large pulmonary embolism (PE) and discuss the factors that predispose to paradoxical embolization following PE.